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Home , Adrenaline, Octopamine

© 2020. Published by The Company of Biologists Ltd | Journal of Experimental Biology (2020) 223, jeb194282. doi:10.1242/jeb.194282

REVIEW The control of metabolic traits by and in Thomas Roeder1,2,*

ABSTRACT recently questioned (Bauknecht and Jékely, 2017). The authors α β Octopamine (OA) and tyramine (TA) are closely related biogenic claim that - and - receptors as well as OA and TA monoamines that act as signalling compounds in invertebrates, receptors were part of the ancestral repertoire of primordial where they fulfil the roles played by and noradrenaline in metazoans; therefore, final clarification of this issue is still pending. . Just like adrenaline and noradrenaline, OA and TA are Finally, similarities in these systems also exist at the level of the ‘ extremely pleiotropic substances that regulate a wide variety of physiological processes that they control. The famous fight-or- ’ processes, including metabolic pathways. However, the role of OA flight response, which is activated in vertebrates by adrenaline and/ and TA in has been largely neglected. The principal aim or NA, and in invertebrates by OA and TA, is the most obvious of this Review is to discuss the roles of OA and TA in the control of example of these physiological similarities. Fight-or-flight metabolic processes in species. OA and TA regulate responses use adrenaline/NA or TA/OA to induce the relevant essential aspects of invertebrate energy by having physiological effects, but they are also characterised by complex substantial effects on both energy uptake and energy expenditure. regulatory inputs that enable their efficient execution. For example, These two monoamines regulate several different factors, such as in vertebrates, the bone-derived system suppresses metabolic rate, physical activity, feeding rate or food choice that have parasympathetic activities in response to , thus strengthening the a considerable influence on effective energy intake and all the fight-or-flight response (Berger et al., 2019). principal contributors to energy consumption. Thereby, OA and TA Numerous studies have shown the regulatory effects of TA and, ’ regulate both metabolic rate and physical activity. These effects especially, OA on almost all aspects of an animal s life, and a should not be seen as isolated actions of these neuroactive number of comprehensive reviews summarise these data (Chase and compounds but as part of a comprehensive regulatory system that Koelle, 2007; Roeder, 1999, 2005; Roeder et al., 2003). However, allows the organism to switch from one physiological state to another. there has been relatively little progress in the differentiation of the effects of OA and TA to date. In some systems, opposing effects of KEY WORDS: melanogaster, Noradrenaline, these substances have been identified, which implies that the Caenorhabditis elegans, Metabolism various functions may be regulated differently according to the proportions of OA and TA present (Alkema et al., 2005; Damrau Introduction et al., 2018; Saraswati et al., 2004; Vierk et al., 2009). These specific Octopamine (OA) and tyramine (TA) are biogenic that are and, in some cases, antagonistic effects of OA and TA will be derived from the and are of the utmost discussed in different parts of this Review. For TA, a particular role importance in invertebrates. These neuroactive substances fulfil the as a neuroactive substance has been highlighted in a number of physiological roles that adrenaline and noradrenaline (NA) perform studies and reviews (Blenau and Baumann, 2003; Cazzamali et al., in vertebrates (Roeder, 1999, 2005). Like adrenaline and NA, both 2005; Lange, 2009; Roeder et al., 2003). However, what at first OA and TA are highly pleiotropic – they are involved in regulating a glance appears to be a surprising variety of effects, largely induced wide range of behaviours, physiological variables and, more by OA, merges into a coherent overall picture on closer inspection. specifically, metabolic pathways. Similarities exist between these In most instances, OA seems to be the messenger that coordinates two signalling systems in invertebrates and vertebrates at various the activities of a number of organs, orchestrating a change from a levels. First, it should be noted that these signalling substances have resting state to a state of higher activity. This concerted action strikingly similar structures: NA differs from OA only in the involves behavioural changes, metabolic adjustments and the presence of an additional hydroxyl group at position three of the optimisation of the performance of various organ systems phenolic ring (Roeder, 1999; Roeder et al., 2003). Furthermore, TA (Adamo et al., 1995; Stevenson and Rillich, 2012). The processes is the biological precursor of OA and adrenaline is produced from that are regulated in this way include those that require substantial NA; thus, each signalling system comprises two messenger resources, such as egg laying (Avila et al., 2012; Lee et al., 2003; Li substances that are not completely independent of one another. et al., 2015). The respective receptors, the α- and β-adrenergic receptors of Central to the combined actions of OA are effects on the vertebrates and the OA and TA receptors of invertebrates, also share circulation, with changes in the rate being the most important substantial sequence similarity, suggesting that they have common outcome. Effects of OA, but also of TA, on heart rate have been evolutionary origins (Fig. 1). However, this interpretation was reported for a number of different species (Fig. 2). In most cases, these amines act to increase the heart rate, whereas for some

1Kiel University, Zoology, Department of Molecular , 24098 Kiel, preparations an inhibitory effect has been shown (Chowanski et al., Germany. 2DZL, German Centre for Research, ARCN, 24098 Kiel, Germany. 2017; Papaefthimiou and Theophilidis, 2011; Pryce et al., 2015). Increased heart rate makes all exchange processes more efficient. *Author for correspondence ([email protected]) Graham Hoyle proposed a hypothesis that describes OA as a

T.R., 0000-0002-3489-3834 messenger compound that modulates a number of different Journal of Experimental Biology

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most important components of energy expenditure, namely Glossary metabolic rate (see Glossary) and physical activity (Fig. 3). Circadian clocks Whenever information is available, I will discuss the effects of Most animals have a circadian rhythm that is controlled by a central the two monoamines separately. circadian clock, which enables the maintenance of rhythm even in the absence of external Zeitgebers (‘time-givers’). Peripheral clocks are Control of , satiety and food selection present in a number of different peripheral organs to regulate local circadian processes. The control of food intake is of central importance to all metabolic Cytoprotective response processes because it regulates the supply of energy. This means that A response induced in cells after exposure to that increases the interaction of hunger and satiation, and the resulting regulation cellular stress resistance. Hunger and reduced food intake are among of food intake, is of great significance when considering the most important inducers of a cytoprotective response. This response metabolism. OA has numerous physiological effects that are is characterised by the induced expression of a defined set of genes. important during a period of hunger. Hunger triggers the release The process of releasing fatty acids from storage triglycerides present in of OA, which induces a suitable physiological response (Tao et al., storage organs ( bodies in , intestinal cells in ). This 2016). Early studies revealed that the administration of exogenous release is necessary to provide energy when needed and is regulated by OA phenocopies the effects of starvation in Caenorhabditis elegans . (Horvitz et al., 1982), and higher body concentrations of OA have Metabolic rate been observed during starvation – Tao and colleagues (2016) The metabolic activity and associated energy consumption that occur in reported a 3–4 times higher OA concentration in fasted C. elegans the absence of physical activity in an organism. It is one of the major components contributing to the overall energy expenditure. compared with well-fed ones. (corpora pedunculata) Invertebrates have evolved a number of different strategies to Regions in the (arthropod) that have a mushroom-like prevent starvation. Starvation activates behavioural responses aimed appearance. The structure is mainly made of fibres of so-called Kenyon at increasing food intake. During starvation, food availability, rather cells and it is known to play a central role in olfactory learning and than the capacity for feeding, is usually the limiting factor. . Therefore, movement to locate new food sources is an appropriate response. Consequently, starvation-induced behavioural responses Messenger compounds that are produced by and reach their target organs via the blood/body fluid. Tyramine and octopamine as well include greater locomotor activity. In D. melanogaster, this as adrenaline and noradrenaline are classic neurohormones, as they are starvation-induced hyperactivity depends on neuronal OA (mostly) produced by nerve cells and address peripheral targets. In production (Yang et al., 2015), as observed previously in C. invertebrates, -like and adipokinetic hormones (AKHs) elegans, where it acts antagonistically to (5-HT). are also neurohormones, as the sites of production are nerve cells. Interestingly, in C. elegans, OA and TA seem to control different Oenocytes aspects of the worms’ complex behaviour in response to starvation, Specialised cells present in insect larvae and adults that are closely associated with fat body cells; they are segmentally organised and show thus acting differentially (Fig. 3). TA promotes reduced locomotion a distinct morphology. Oenocytes are -like cells that are to allow feeding, and OA promotes increased locomotion in involved in energy metabolism and the of cuticular response to fasting to allow searching for new food sources hydrocarbons and pheromones. (Churgin et al., 2017). However, the role of OA in the context of Supraoesophageal and suboesophageal ganglion feeding in invertebrates is still controversial, because food intake is a The two main parts of the insect brain, which can exist either as multifaceted behaviour: starvation-induced hyperactivity is structurally independent units or as fused brain. Most of the higher brain functions are provided by structures of the supraoesophageal ganglion, obviously a very important aspect of the overall response to while one of the main functions of the suboesophageal ganglion is in the starvation, but it is not necessarily causally related to increased food control of the mouth parts. intake. Despite the numerous different approaches that have been developed to quantify food intake, it is only very recently that reliable and reproducible approaches have been published (Shell et al., 2018). Previous difficulties in reliably monitoring daily food behavioural and physiological properties in order to transform the intake might be one reason why some studies show that food intake animal into a state of higher activity; this is known as the indeed depends on OA in D. melanogaster (Li et al., 2016), whereas orchestration hypothesis (Hoyle, 1985; Libersat and Pflueger, other studies do not show this dependency (Yang et al., 2015). 2004). These disparate OA-mediated effects serve to coordinate The behavioural response to starvation is complex. As discussed organ function, enabling a coherent physiological response at the above, starvation-induced hyperactivity enables the search for new organismal level. However, to date, the focus of most studies has food sources. Therefore, persistence in following an odour trace that been on the behavioural and motor effects of OA and TA, whereas leads to a food source is an adaptive response, but it is necessary to their influence on metabolism has been little studied. Nevertheless, inhibit odour tracking in order to start feeding. In D. melanogaster, there is considerable evidence that this aspect of OA/TA action is the activation of OA-containing VPM4 neurons reduces persistent important for the overall performance of the organism (Li et al., odour tracking, which might be the signal to start feeding (Sayin 2016; Roeder, 2005). Therefore, this Review focuses on the effects et al., 2019). Moreover, targeted manipulation of octopaminergic of both of these neuroactive amines on metabolism. Aspects of their VPM4 activity shows that these neurons promote feeding by activity that affect behaviour will be considered if they are directly increasing the proboscis extension response in adult flies (Youn connected to energy gain or energy expenditure. The relationship et al., 2018). Buckemüller and colleagues (2017) observed a similar between energy intake and energy expenditure is of central effect of octopaminergic signalling on proboscis extension, and importance for the regulation of metabolic processes, and both of therefore on feeding, in honey bees. Indeed, this OA-induced these variables are directly and indirectly influenced by OA and TA. increase in feeding appears to be a general phenomenon in insects Therefore, I first discuss the different contributions of OA and TA to (Cohen et al., 2002). In D. melanogaster larvae, neuronal circuits energy intake and move on to discuss their roles in modulating the involving octopaminergic VUM neurons in the suboesophageal Journal of Experimental Biology

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Signalling molecules Receptors Fig. 1. Structure of the octopaminergic/tyraminergic system of invertebrates and the noradrenergic/adrenergic system of Invertebrates D. melanogaster C. elegans vertebrates. The chemical structures of octopamine (OA), tyramine (TA), noradrenaline (NA) and adrenaline are given on the left. The corresponding receptors are listed on the right. For the invertebrate OA/ Oct-TyrR Ser-2 TA systems, receptors from and TyrR2 Tyra-3 Caenorhabditis elegans are displayed; for vertebrates, the canonical TyrR3 Tyra-2 NH2 set of adrenergic receptors is given. With the exception of Lgc-55, which HO Lgc-55 is a TA-gated chloride channel, all other receptors belong to the Tyramine G-protein coupled receptor (GPCR) superfamily. Oct-TyrR, octopamine–tyramine receptor; TyrR, tyramine receptor; OctR, OH octopamine receptor; Ser-2, tyramine receptor 1; Tyra, tyramine Octα-1R Octr-1 receptor; Lgc-55, tyramine-gated chloride channel 55; Octr-1, Octα-2R Ser-3 octopamine receptor 1; Ser-3, octopamine receptor; Ser-6, octopamine Octβ-1R Ser-6 receptor; α, alpha-; β, beta-adrenergic receptor. Octβ-2R Octβ-3R NH2 HO Octopamine

Vertebrates

OH

HO

NH 2 α1A β1 HO α β Noradrenaline 1B 2 α1D β3 α2A OH α2B α2C HO

HN HO CH3 Adrenaline ganglion (see Glossary) are involved in the increase in feeding the possible food range, but it is associated with a higher risk of in response to hunger, while sub-circuits also comprising infection. This shift towards a more comprehensive food range octopaminergic neurons prevent overfeeding and are therefore (albeit one that is associated with a certain risk) seems to be a associated with satiety (Zhang et al., 2013). general mechanism in response to starvation. OA is the Besides the initiation of feeding, additional behaviours are altered (see Glossary) that mediates a shift towards in response to starvation that are highly relevant for food intake attraction to a greater range of foods, which is observed during (Fig. 3). For example, prior to the start of feeding, an organism must starvation (Rengarajan et al., 2019). Furthermore, OA appears to decide what to eat and what not to eat. Starvation influences foster decision making in situations where various options are this decision in two different ways: it sensitises sugar taste and available (Claßen and Scholz, 2018). For example, mated females desensitises bitter taste (Lin et al., 2019). Thus, starvation changes require food with a relatively high protein content in order to the acceptance of food sources dramatically, which leads to optimise their fecundity; in D. melanogaster, they show protein- acceptance of otherwise rejected food, increasing energy intake in seeking behaviour that is mediated by octopaminergic neurons in periods of food scarcity. Drosophila melanogaster, like most response to starvation (Tian and Wang, 2018). In summary, it can be animals, avoid bitter food sources because this taste is often concluded that OA is a classic hunger signal that modulates various associated with toxicity. However, starvation reduces the sensation aspects of food intake. Its secretion leads to the ingestion of larger of bitterness and therefore increases the acceptance of bitter-tasting quantities of food to provide the required amount of energy. food sources. OA- and/or TA-secreting neurons (OA-VL) potentiate this bitterness sensation, and upon starvation they reduce their Energy expenditure: the regulation of physical activity by OA activity, thereby reducing the sensation of bitterness (LeDue et al., and/or TA 2016). A similar adjustment of food source-associated sensory As discussed above, OA plays a crucial role in the control of food inputs was described for C. elegans, which can react differently to intake and therefore in the regulation of energy supply. However, CO2 such that is it attractive, repulsive or neutral. CO2 is thought to energy intake is normally balanced by energy consumption, which represent an ambiguous signal as it is produced not only by the comprises two main components: physical activity and metabolic normal food bacteria C. elegans depends on but also by potential rate. Physical activity is easy to measure and is subject to pathogens. Therefore, shifting from aversion to attraction increases behavioural control mechanisms, but the regulation of metabolic Journal of Experimental Biology

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Fig. 2. Interaction of OA and TA with different peripheral organs and with the central clock. Effects of OA (blue arrows pointing towards the target organs) and TA (red arrows pointing towards the target organs) are shown. For Heart some of these interactions, both OA and TA affect the Circadian clock corresponding peripheral organ. Very few systems + ? (intestine, hormones, central clock) have been shown to influence the level of either of these compounds or of the Intestine +/− + enzymes that are responsible for OA and TA synthesis. Symbols close to the targets indicate whether a positive (+) ? +/− Hormones or a negative (−) effect has been reported. Question marks ? + ? e.g. ILPs, AKH, JH indicate either that it is not known in which direction the modulation occurs or that the terms activation and inhibition are not meaningful. The arrow with the mixed colours from + the circadian clock to the OA/TA system indicates that the +/− ? OA-TA activity of the enzyme producing both compounds cycles in a circadian rhythm. ILP, insulin-like ; AKH, + adipokinetic ; JH, juvenile hormone. Oenocytes Muscles

+ ?

? ? ?

Trachea

Fat body Haemocytes rate is far less well understood. In this section, I will discuss the containing neurons located in the sub-oesophageal ganglion effects of OA and TA on physical activity, which directly impacts activate neurons that, in turn, control these energy expenditure. It should be mentioned that the body of GABAergic mushroom body output neurons (MBON). Either information dealing with the effects of OA on the regulation of inhibition of the octopaminergic or dopaminergic neurons or physical activity is much more comprehensive than that of TA on activation of the GABAergic neurons reduces the duration of flight the corresponding behaviours (Fig. 2). episodes (Manjila et al., 2019). These positive effects of OA on Flight is the most energy-intensive means of movement in insects. various aspects of flight performance occur concurrently with OA regulates flight behaviour at a number of levels, thus contributing modulation of visual information processing (Suver et al., 2012). to this important component of energy expenditure (Orchard et al., This means that OA enables efficient insect flight because many 1993). Drosophila melanogaster, like other insects, fly at a relatively essential aspects of this behaviour are under direct octopaminergic constant cruising speed, independent of hormonal influences (and thus control. Thus, there is a clear and direct relationship between OA/ also mostly independent of OA levels). However, OA affects the rate of TA and the most energy-intensive means of insect movement. acceleration, thus altering the time taken to reach the appropriate flight Terrestrial locomotion is another major cause of energy speed. This is especially relevant for more complex flight manoeuvres, expenditure. Higher OA concentrations are associated with an as they are characterised by frequent changes in direction and flight increase in walking activity in flies and other arthropods, and in speed. Thus, although OA has no impact on normal flight speed, movement speed in C. elegans.InC. elegans, this effect of OA on through its effects on acceleration it should have a major impact on movement has been reported several times (Churgin et al., 2017; overall flight speed and performance (van Breugel et al., 2014). Flies Donnelly et al., 2013). As discussed above, starvation-induced, OA- deficient in the production of OA show significant changes in dependent higher physical activity seems to be a general phenomenon additional major components of flight behaviour: important in insects. A series of very elegant experiments performed in Graham parameters of flight control, namely flight initiation and length of Hoyle’s laboratory set the stage for a better understanding of the role of flight episodes, critically depend on this . Interestingly, TA also OA in the initiation and maintenance of all kinds of insect movement. appears to be an integral part of the flight control system in insects; at This work showed that local application of OA into defined regions of high concentrations, TA acts antagonistically to OA. Nevertheless, the thoracic ganglia of locusts induces different types of rhythmic these differential effects of OA and TA on these flight-related traits are behaviours, such as flight, walking or egg deposition (Sombati and not simply antagonistic, as they could only be observed at high TA and Hoyle, 1984). Only very recently, comparable studies with Drosophila concurrent low OA concentrations (Brembs et al., 2007). Thus, long melanogaster have elucidated the cellular circuitries underlying these periods of uninterrupted flight that are necessary to find new places and responses. Based on the early studies performed in the Hoyle lab, Jay new resources critically depend on high OA concentrations. These Hirsh’s laboratory showed that exogenous OA induces stereotypic flight periods are particularly energy demanding. movement programmes, even in a highly reduced, ‘headless’ Mechanistically, OA-containing neurons are part of a complex Drosophila melanogaster model (Yellman et al., 1997). Thus, in neuronal network also comprising dopaminergic and GABAergic many insects and other arthropods, OA increases movement and neurons within the mushroom bodies (see Glossary). OA- general arousal, thereby substantially increasing energy expenditure. Journal of Experimental Biology

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Energy expenditure it applies also to exothermic animals, including all invertebrates. The resting metabolic rate is the sum of metabolic activities of all Metabolic rate Physical activity organ systems in an animal in the absence of movement activity. Usually, the metabolic rate accounts for a large percentage of the +++/− overall energy expenditure. OA-deficient D. melanogaster show several different metabolic adaptations. For example, these flies develop severe obesity, which is characterised by a body fat mass that is substantially higher than the average (Bullman et al., 2017; Li et al., 2016). This phenotype probably results from an imbalance in OH energy intake and expenditure. Interestingly, these OA-deficient animals show lower energy intake than average, because of lower dietary intake, but they also demonstrate lower energy expenditure because of lower physical activity and resting metabolic rate NH (Li et al., 2016). However, the underlying molecular mechanisms 2 NH2 HO HO have yet to be established. Ectopic activation of OA release by Octopamine (OA) Tyramine (TA) thermogenetic activation of octopaminergic neurons induces the opposite phenotype, which is characterised by substantially lower body fat mass (Li et al., 2016). This phenotype resembles the situation observed in humans who have a dysregulation of adrenergic signalling, because adrenaline and NA directly regulate lipolysis (see Glossary) in fat cells (Bartness et al., 2014; +++/− Lafontan and Berlan, 1993). Fasting in vertebrates induces an increase in NA/adrenaline Feeding rate Appetite, release from autonomous neurons, which mirrors the situation in food choice invertebrates, where OA is also released in response to starvation Energy intake (Wang et al., 2016). However, the molecular mechanisms that underlie the transduction of the modulatory effects of OA and/or TA Fig. 3. Effects of OA and TA on the most important components on body fat mass are poorly characterised in invertebrates. At contributing to either energy expenditure or energy intake. OA (blue present, direct effects on the storage organ (the fat body) and indirect arrows) and TA (red arrows) affect systems contributing to energy expenditure (metabolic rate and physical activity) as well as those responsible for energy effects via, for example, release, cannot be intake (feeding rate, appetite, food choice). Symbols indicate whether positive differentiated. Adipokinetic hormones (AKHs), which are the (+) or negative (−) effects have been reported. invertebrate equivalents of , are the most potent lipolytic hormones (Arrese and Soulages, 2010). Similar to glucagon release, The effects of OA on movement induction and maintenance in AKH release provides energy-rich substances, such as fatty acids invertebrates are paralleled by those observed in studies of human and carbohydrates. AKH directly acts on the fat body via specific physiology. As observed in humans, flies respond to endurance receptors (Grönke et al., 2007), thereby inducing release of fatty training with improvements in walking speed and cardiac acids. In experimentally amenable insects, such as locusts, a direct performance. This adaptive reaction is completely dependent on effect of OA on lipolysis from the fat body has been reported OA and can be mimicked by the intermittent, daily application of (Orchard et al., 1982). This direct effect resembles the situation this neuroactive substance (Sujkowski et al., 2017; Sujkowski and observed in C. elegans, where OA, together with 5-HT, can induce Wessells, 2018). lipolysis directly from the major storage organs (Noble et al., 2013). Surprisingly, in D. melanogaster, the presence of an intestinal I discuss the interaction between OA and the release of AKHs in microbiome also affects movement activity, and this link requires more detail below. octopaminergic signalling, representing an impressive example of a Whether there is a direct physiological effect of OA and/or TA functional gut–brain axis, in which OA is of central importance that is mediated by specific receptors present on target tissues (Schretter et al., 2018). The authors showed that germ-free animals such as the fat body or the oenocytes (see Glossary) is still a matter exhibit hyperactive locomotor activity. This phenotype is rescued of debate; in D. melanogaster, such an interaction remains to be by reassociation with a functional microbiota, and even by unequivocally shown. The major storage organ of insects, the monoassociation with a particular member of the microbiota, fat body, which is the functional equivalent of adipose namely with Lactobacillus brevis. Furthermore, a single bacterial tissue, is a direct target of OA, at least in a number of experimentally enzyme, the xylose isomerase, recapitulates this rescue. Ectopic more amenable insects, such as locusts or cockroaches. For application of OA, as well as activation of octopaminergic neurons, example, OA was shown to induce the release of fatty acids from abrogates these effects of the xylose isomerase (Schretter et al., fat bodies isolated from locusts in a dose-dependent manner 2018). It has to be kept in mind that the relevance of the microbiota (Orchard et al., 1982). Other data obtained with locusts, crickets or for different physiological processes differs vastly between insect moths complemented this finding, showing that, as in vertebrates, species (Hammer et al., 2017). OA (the invertebrate equivalent of an adrenergic signalling compound) directly activates and carbohydrate release Effects of OA and TA on metabolic performance and from this major energy-storing organ (Arrese and Soulages, 2010; metabolic rate Fields and Woodring, 1991; Meyer-Fernandes et al., 2000; Orchard Metabolic activity (or more precisely, the basal or resting metabolic et al., 1993; Park and Keeley, 1998). OA also regulates the liberation rate) is defined as the rate of energy expenditure at rest (McNab, of carbohydrates from stored in the fat body of

1997). This definition was introduced for endothermic animals, but cockroaches (Fig. 2). In vitro incubation of isolated fat bodies Journal of Experimental Biology

5 REVIEW Journal of Experimental Biology (2020) 223, jeb194282. doi:10.1242/jeb.194282 with OA results in the activation of , which parallel with the effects of nutritional interventions, such as dietary is required for the release of trehalose, one of the most important restriction, which lead to a reduction in circulating insulin energy-containing compounds in the haemolymph (Park and concentration and lower resting metabolic rate (Romey-Glüsing Keeley, 1998). It has to be kept in mind that, in D. melanogaster, et al., 2018). A lower circulating insulin concentration would result such a direct effect has yet to be shown. One particular OA receptor, in metabolic changes, including lower uptake and greater Octβ-2R, is expressed at significant levels in the fat bodies of larvae mobilisation of fat and glycogen. and adults (El-Kholy et al., 2015; Leader et al., 2018); this receptor Recent studies with C. elegans have shown that TA affects insulin could mediate the direct effect of OA on the fat body. In addition, a signalling not only at the TA release site but also at the level of the study that comprehensively mapped the potential release sites of insulin-responsive cells. In C. elegans, TA is released in response to OA-containing neurons in D. melanogaster revealed that almost all short but potent stress signals, which induce the fight-or-flight organs can be targeted by these neurons. This implies that almost all response (Alkema et al., 2005; Roeder, 1999, 2005). This release of insect organs can be direct targets of OA (and TA) action (Pauls TA activates insulin signalling in C. elegans, especially targeting the et al., 2018). Despite the uncertainties regarding whether OA can intestinal cells, thereby inhibiting the nuclear translocation of FoxO/ directly induce the release of fatty acids from peripheral stores in daf-16, which blunts the cytoprotective response (see Glossary) D. melanogaster, this appears to be the case for other invertebrates, usually induced by these proteins (De Rosa et al., 2019). Initial including locusts, crickets, cockroaches and moths (see above), as studies imply that this interaction between the octopaminergic/ well as C. elegans. In this last species, OA is released from RIM tyraminergic and insulin systems is not unidirectional, but organised neurons in response to starvation, and it seems to interact with Ser-3 in a reciprocal fashion. The activity of chico, the major insulin receptors in the intestine, an important storage organ (Noble et al., receptor substrate, regulates OA/TA metabolism, which adds a level 2013; Tao et al., 2016). of complexity (Adonyeva et al., 2016). In addition to release of insulin, that of other hormones is also Regulation of hormone release by OA and TA in the control of regulated by OA/TA. The corpora allata, which produces the juvenile metabolic status hormone of insects, expresses OA receptors. In larvae, OA The most important means whereby OA and TA regulate the stimulates the release of juvenile hormone (Rachinsky, 1994), and this metabolic status of an animal are likely to be through their effects on may also occur in D. melanogaster, because OA secretion from sites the release of other hormones (Fig. 2). Insulin and glucagon in close to the corpora allata has been reported (Pauls et al., 2018). Higher vertebrates and insulin-like peptides and AKH in invertebrates are juvenile hormone concentrations may be associated with higher central players in the control of metabolic traits. Whereas the release metabolic rate and therefore with energy expenditure. This proposition of insulin and insulin-like peptides triggers the switch towards the is supported by studies conducted in the beetle Dermestes maculatus, storage of energy, glucagon and AKH induce exactly the opposite which showed that juvenile hormone analogues substantially (Ahmad et al., 2019; Gáliková et al., 2015; Hoffmann et al., 2013; upregulate metabolic rate (Sláma and Krypsin-Sørensen, 1979). In Nässel and Vanden Broeck, 2016; Straub and Sharp, 2012). Thus, burying beetles, a correlation between juvenile hormone concentration modulation of the release of either insulin-like peptides (ILPs) or and metabolic rate (Trumbo and Rauter, 2014) was also identified, AKH by OA and TA should have a major impact on the metabolism which further supports the hypothesis that OA affects metabolic status of the organism. Consequently, the regulation of insulin-secreting by regulating juvenile hormone release. The corpora cardiaca, another cells appears to be the most important mechanism whereby hormone-secreting structure that substantially affects metabolism in adrenergic/octopaminergic/tyraminergic signalling systems exert D. melanogaster, produces and releases AKHs, which (as discussed their effects on major metabolic parameters (Ahmad et al., 2019; above) are the most important energy-liberating hormones in insects. Nässel et al., 2015; Straub and Sharp, 2012). Indeed, NA and However, it remains to be confirmed whether OA induces AKH release adrenaline have long been known to inhibit the release of insulin from from the corpora cardiaca. A series of studies performed more than pancreatic islets (Porte and Williams, 1966). The blunting of 20 years ago utilizing experimentally amenable insects such as locusts adrenergic signalling in vertebrates induces a set of predictable showed that OA application induces cAMP production in the corpora phenotypic changes, including the induction of obesity, and cardiaca as well as AKH release from this organ (Orchard et al., 1993; OA-deficient D. melanogaster also show an obese phenotype, with Downer et al., 1984). This dependency could not be demonstrated lower haemolymph glucose concentrations, which are presumably in D. melanogaster (Ahmad et al., 2019). Interestingly, a different caused by the highercirculating insulin concentrations. Therefore, OA type of interaction between the octopaminergic and the AKHergic may reduce insulin secretion (Bullman et al., 2017; Li et al., 2016). systems has recently been elucidated. AKH release, which is triggered Regarding the underlying mechanisms, it has been proposed that OA by starvation, induces a set of behavioural responses. Among them, binds to specific receptors, especially the OAMB receptor (Octα-1R), hyperactivity takes a central role as it allows the search for new which is present on insulin-like peptide 2 (dILP2)-expressing cells resources. Here, AKH directly controls OA-containing neurons that are in the pars intercerebralis (PI) of the adult fly brain (Crocker et al., necessary to translate starvation into hyperactivity (Yu et al., 2016). 2010); dILP2 is the most important insulin-like peptide in D. melanogaster (Park et al., 2014). However, it remains unclear Impact of OA and TA on circadian rhythms and the sleep/ whether the inhibitory effects of OA on dILP release from the PI cells wake cycle are indeed mediated by the OAMB receptor or whether other receptors Circadian rhythms consisting of rest/sleep phases and activity phases are also involved; it is also unclear how this signalling system operates are seen throughout the entire animal kingdom. At the cellular level, to control ILP release (Nässel et al., 2013, 2015). the rhythm is controlled by an evolutionarily conserved system Modification of insulin secretion is a powerful and effective way composed of only a few components that regulate the periodic of regulating the metabolic state of an animal. Flies missing the most activation of transcription (Allada and Chung, 2010). The pioneering important ILPs have a lower basal metabolic rate, implying that the work in D. melanogaster that led to the identification of the clock regulation of insulin secretion affects this important aspect of energy genes was honoured in 2017 with the Nobel prize awarded to Jeff expenditure (Zhang et al., 2009). Such regulation also occurs in Hall, Michael Rosbash and Michael Young (Sehgal, 2017). Journal of Experimental Biology

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Circadian clocks (see Glossary) usually show a hierarchical behaviours, the number of studies explicitly showing effects of TA organisation, with a central clock located in the brain controlling in the control of metabolic traits is much lower than those showing various peripheral clocks operating in different organs (Dibner et al., effects of OA. It is still unclear whether this discrepancy reflects 2010). These clock systems are responsive to a number of different actual differences in the importance of the two compounds for hormonal signals, which naturally have a major influence on controlling metabolism or whether this imbalance results from metabolic processes. Moreover, the clock output and the control of biased study designs that focus more strongly on OA. The effect of sleep/wake periods is interconnected with feeding behaviour: OA on metabolic traits seems to be in changing from a behavioural starvation suppresses sleep, and sleep deprivation promotes food and metabolic state of rest to a state of high activity. This change intake (Keene et al., 2010). Therefore, the circadian rhythm and the affects the two most important states of metabolism: basal metabolic associated sleep/wake cycle are of central importance to the rate and motor activity. As a result, energy consumption increases, performance of metabolic systems. The resting phase, and especially and the storage of energy as fat and glycogen decreases. These sleep, are associated with substantial reductions in energy expenditure, effects parallel quite closely those of NA and adrenaline in which is important for the minimisation of metabolic waste. vertebrates. Moreover, OA increases wakefulness, which is In vertebrates, adrenaline and NA not only affect circadian rhythm commonly associated with an increase in metabolic activity. In and sleep quality but also their plasma concentrations cycle in a addition, OA and TA directly affect energy intake. Because OA is a circadian manner (Linsell et al., 1985) and regulate important starvation signal, one of its major roles is to fulfil energy demands physiological functions accordingly (Scheer et al., 2010). by increasing food intake. In summary, OA and TA are signalling Adrenaline/NA secretion modulates peripheral clock systems compounds that release invertebrates from an economical resting (Terazono et al., 2003), implying that there is a complex feedback state and direct their metabolism towards a more active state that between the circadian clock and adrenergic/noradrenergic signalling. requires more energy. In D. melanogaster, OA promotes wakefulness via regulation of Despite the importance of metabolism for overall fitness, the activity, whereas OA deficiency promotes sleep impact that OA and TA have on it is understudied and certainly (Crocker and Sehgal, 2008). These wakefulness-promoting effects of deserves much more attention than it has received so far. A major OA are mediated by octopaminergic ASM neurons and require their weakness of studies performed in this field is the exclusive focus on interaction with insulin-producing cells, in which binding to the the two major models, the fruit fly Drosophila melanogaster and the OAMB receptor (Octα-1R) alters potassium conductance and soil Caenorhabditis elegans. Thus, studies using other increases cAMP levels (Crocker et al., 2010). The wakefulness- organisms, including representatives of the large and mostly promoting effects that are mediated through OA secretion, the OAMB unexplored group of lophotrochozoans, are highly appreciated; it receptor and insulin-producing cells are known to be independent of is important to know whether specific mechanisms identified in insulin, because alterations in insulin secretion have no effect on sleep D. melanogaster or C. elegans are of general relevance or whether (Erion et al., 2012). These effects of OA on sleep have also been found they are specific for these models. In addition, some major questions in D. melanogaster larvae, in which an increase in OA signalling in the field remain to be answered. These questions cover various reduces sleep. In this scenario, sleep allows the maintenance of stem facets of octopaminergic and tyraminergic neurotransmission, cell activity, which ensures proper development (Szuperak et al., 2018). ranging from understanding the general organisation of these Similar to the role of adrenaline in vertebrates, the modulation of systems to determining the effects induced at particular target sites. peripheral physiology in D. melanogaster, which is subject to At a higher organisational level, it is still not understood whether the circadian rhythms, appears to depend on OA (Schendzielorz et al., corresponding systems have a hierarchical organisation or whether 2015). However, the role of OA in mediating the effect of the OA and TA are transmitters in a complex system of inter-organ circadian clock on peripheral targets is more complex than expected, communication with multiple feedback loops. How do OA/TA- because the expression of OA receptors, such as OA2 (Octβ-1R) and containing cellular systems interact with other hormonal systems in OAMB (Octα-1R), cycles in cells responsible for the central clock of invertebrates, and how does this interaction give rise to a concerted D. melanogaster (Kula-Eversole et al., 2010). Indeed, OA has and expedient response of the organism? Possibly the most enigmatic substantial time- and light-dependent effects on the properties of parts issue is how octopaminergic and tyraminergic signalling systems are of the central circadian clock of flies. Large lateral–ventral neurons controlled in the animal. Are the two compounds released together or (l-LNvs) are important parts of the central clock in D. melanogaster, is there a differential release allowing for a differential control of the and they are wake promoting. They integrate information from light two systems? Last but not least, our understanding of the different and OA-containing neurons, but also from (DA)- roles of the numerous specific receptors for OA and TA is still very containing neurons. OA, similar to DA, modulates the cAMP level limited. This is especially puzzling in those systems where different in these cells, thereby modulating their properties substantially. The receptors are expressed in the same cells. As already mentioned, action of these two transmitters is strongly context dependent; for studies from a variety of animals should be excellently suited to example, light and the clock cycle alter the modulatory effect of OA ultimately clarify these unresolved problems. (Shang et al., 2011). The network that exists between the central clock and OA/TA production and OA/TA action is even more complex, as it Acknowledgements was demonstrated that Tdc2, the enzyme that produces TA from I would like to thank my group (the Department of Molecular Physiology at the University of Kiel), especially Britta Laubenstein and Christiane Sandberg for their tyrosine and that is also required to produce OA, is present in central continuous support. clock neurons (Fig. 2). Furthermore, Huang and colleagues (2013) showed that Tdc2 cycles with a circadian rhythmicity, both at the Competing interests transcript and the protein level (Huang et al., 2013). The author declares no competing or financial interests.

Funding Conclusions The research in the laboratory was supported by the Deutsche The two monoamines OA and TA play a central role in the Forschungsgemeinschaft (DFG, SFB 1182, Project C2) and the Bundesministerium regulation of invertebrate metabolism. As for almost all systems and für Bildung und Forschung (Project DroLuCa). Journal of Experimental Biology

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